Infected cells can recognize the presence of a virus by sending out signals which result in the transcription and secretion of type I interferon (IFNα and IFNβ). IFNα is a family of thirteen polypeptides (subtypes) coded by different genes. IFNβ is a glycoprotein produced by a single gene. Different cell types produce both IFNα and IFNβ (1, 2).
Viral infection is the main stimulus for the production of type I interferon, although there are other factors which can increase its synthesis, such as bacterial components, double chain RNA, growth factors and other cytokines (1). In addition to having its antiviral effect, IFNα can interact with certain cytokines and with T cells regulating the growth and differentiation of the cells in the immune system (3). IFNα genes are expressed as a matter of course in human tissue in healthy individuals (4), while the expression of particular subtypes is restricted to certain cell types (5, 6). The induction of IFN by viruses is mainly regulated at transcription level. The specific activation of transcription occurs through the interaction of cell factors induced by viruses with the domains regulating the promoters of IFNα genes (7).
All IFNα and IFNβ subtypes have a common receptor at the cell surface. Competitive binding tests at the receptor for different IFNα subtypes indicate that all of these combine at the same receptor, but with different affinities (8). The biological activity of the different subtypes of IFNα is little known. The IFNα 5 and IFNβ 8 interferon subtypes appear to be those having the greatest antiviral activity. Antiproliferative response also differs between the different subtypes (9). In humans unstimulated peripheral blood mononuclear cells express different IFNα subtypes (10).
A common mechanism for the persistence of viral infection is avoidance of the IFN system. Many viruses have developed strategies to avoid the antiviral effects of IFN. Specifically, a selective defect in the production of IFNα has been described in monocytes infected by human immunodeficiency virus (11).
Hepatitis C virus (HCV) is a single chain RNA virus which results in chronic infection in more than two thirds of persons infected. The prevalence of infection by HCV is around 2 to 3% in the population of the West. Studies performed in Europe show that 33% of patients with chronic HCV infection develop cirrhosis in a mean period of less than 20 years (12). A significant proportion of these patients develop liver cancer, with an annual incidence of 1.4% (13). It has been difficult to find the reason for the high level of persistence of HCV infection. The high rate of mutations in the virus and the production of a predominant profile of Th2 cytokines in comparison with Th1 have been described as being responsible for this high level of persistence by the infection. Treatment with IFN induces a sustained response in around 30% of patients with chronic hepatitis C. The mechanism responsible for response or non-response to treatment with IFN is little understood.
The IFN system has only been studied in chronic HCV infection. There is no appropriate animal model for chronic HCV infection, and, because of this, investigations performed on humans are the only source of information on the pathophysiology and pathogenesis of chronic hepatitis C. This invention describes the expression of IFNα and IFNβ genes in the liver and in the peripheral blood mononuclear cells (PBMC) in healthy controls and patients with chronic hepatitis C. In addition to this we have analysed the IFNα subtype expressed in normal liver tissue and the liver tissue of patients with chronic hepatitis C. Expression of the different IFNα subtypes has also been analysed in PBMC in healthy controls and patients with chronic hepatitis C.